Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Mol Pharm. 2012 Oct 1;9(10):2812-8. doi: 10.1021/mp3001183. Epub 2012 Sep 17.
Colloidal drug and prodrug conjugates have unique targeting characteristics for tumor vasculature from the blood and for the lymphatics draining a tissue injection site. Tioguanine and tioguanine-generating prodrugs have been investigated as anticancer and immunosuppressive agents, including use in cancer immunotherapy. Recently we developed block copolymers of poly(ethylene glycol)-bl-poly(propylene sulfide) that self-assemble in aqueous solutions to form micellar structures. Since the polymers carry a free terminal thiol group resulting from the ring-opening polymerization of the propylene sulfide monomer, we sought to prepare prodrug block copolymers with tioguanine linked by a reduction-sensitive disulfide bond. The synthesis involved a disulfide exchange between the oxidized form of tioguanine and the polymer. Spectroscopic data is presented to support the proposed reaction. The polymers self-assembled when dispersed in water to form tioguanine prodrug micelles with a size range between 18 and 40 nm that released tioguanine in response to cysteine and serum as shown spectroscopically. In comparison with a poly(ethylene glycol) prodrug polymer, we show that the rate of tioguanine release can be controlled by changing the poly(propylene sulfide) block length and that the tioguanine remains bioactive with cultured cells.
胶态药物和前药缀合物具有独特的靶向特性，可靶向血液中的肿瘤血管和组织注射部位的淋巴管。硫鸟嘌呤和产生硫鸟嘌呤的前药已被用作抗癌和免疫抑制药物，包括用于癌症免疫治疗。最近，我们开发了聚（乙二醇）-b-聚（丙烯硫醚）的嵌段共聚物，它们在水溶液中自组装形成胶束结构。由于聚合物带有游离的末端硫醇基团，这是丙烯硫醚单体开环聚合的结果，因此我们试图制备通过还原敏感的二硫键连接硫鸟嘌呤的前药嵌段共聚物。该合成涉及硫鸟嘌呤的氧化形式与聚合物之间的二硫键交换。提出了支持该反应的光谱数据。聚合物在水中分散时自组装，形成大小在 18 至 40nm 之间的硫鸟嘌呤前药胶束，可通过光谱法检测到在半胱氨酸和血清的作用下释放硫鸟嘌呤。与聚（乙二醇）前药聚合物相比，我们表明可以通过改变聚（丙烯硫醚）嵌段长度来控制硫鸟嘌呤的释放速率，并且硫鸟嘌呤在培养细胞中仍然具有生物活性。
